This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mutations in the RNase H2 proteins are an underlying cause of inherited forms of systemic lupus erythematosus (SLE) and Aicardi-Gouti[unreadable][unreadable]res syndrome (AGS), implicating dysfunction of these proteins in an aberrant immune response. Evidence suggests that the pathogenesis of these diseases is likely related to the accumulation of non-processed DNA and RNA intermediates after cell death, which leads to the activation of innate immunity. Human RNase H2 hydrolyzes RNA within RNA:DNA hybrids, but functions as part of a larger, heterotrimeric complex. Thus, it represent a specific example of the general phenomenon that activities of cellular nucleases are often controlled by subunit associations within a larger complex, and that dysfunction of these complexes leads to disease. The goal of this project is to determine how the catalytic activity of this enzyme complex is regulated and how the disease-causing mutations lead to biological dysfunction.